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Département d’Athérosclérose, Institut Pasteur de Lille, Institut National de la Santé et de la Recherche Médicale Unité 545, and Université de Lille, F-59019 Lille, France
Address all correspondence and requests for reprints to: Bart Staels, Institut Pasteur de Lille, Département d’Athérosclérose, Lille F-59019, France. E-mail: bart.staels{at}pasteur-lille.fr.
The farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily of ligand-activated transcription factors. Although initially farnesol metabolites were identified as natural FXR ligands (1), the major breakthrough in FXR biology came with the demonstration that bile acids bind to and activate this nuclear receptor (2). Bile acids are synthesized in the liver from cholesterol and secreted via the bile into the small intestine in which they facilitate the digestion and absorption of dietary lipids. Bile acids subsequently return to the liver to complete the enterohepatic recirculation process (for review, see Ref. 3). In accordance, FXR is expressed at high levels in the liver and small intestine, in which it regulates bile acid homeostasis on activation by these natural ligands. Consequently, the main role of FXR is to protect the liver from the deleterious effect of bile acid overloading by inhibiting their biosynthesis and stimulating their excretion. In addition, the characterization of FXR-deficient (FXR–/–) mice has established a role for FXR in the regulation of lipid metabolism (4). FXR–/– mice display elevated plasma and hepatic cholesterol and triglyceride levels. Moreover, FXR regulates the expression of several apolipoproteins involved in the transport and metabolism of lipids (for review, see Ref. 3). Earlier this year several reports appeared implicating FXR in the control of hepatic and peripheral glucose homeostasis (5, 6, 7, 8). FXR–/– mice display an accelerated hepatic response on feeding a high carbohydrate diet and develop peripheral insulin resistance. Collectively, these observations establish a critical role of FXR in the control of cholesterol, lipid, and glucose metabolism.
Based on these data, FXR appears as a potential drug target for the treatment of metabolic disorders, especially those related to the metabolic syndrome. The effects of FXR activation using synthetic ligands on metabolic disorders have already been tested in mice. Treatment of diabetic mice with the synthetic FXR ligand GW4064 improves insulin resistance, hyperglycemia, and hyperlipidemia (6, 8). In addition to bile acids, other endogenous FXR ligands have been identified, such as polyunsaturated fatty acids (9), certain bile acid metabolites (10), and oxysterols, which are intermediates in the synthesis of bile acids and steroid hormones (11).
In this issue of Endocrinology, Wang et al. (12) identify a new natural ligand of FXR, i.e. the androgen metabolite androsterone. Androgens are male sex hormones that play physiological roles in the development of the male gonads and the secondary sex characteristics (13). Testosterone, the main androgen, is produced by the testis. However, testosterone itself is a poor activator of the androgen receptor (AR), another nuclear receptor, and requires conversion in the active dihydrotestosterone, a potent AR activator. Testosterone metabolism results also in the formation of androgen metabolites with lesser activity. Among these is androsterone, a steroid metabolite that seems to lack activity toward the AR. It now turns out that androsterone does activate a nuclear receptor: FXR. These data are in line with those from another study reporting that androsterone up-regulates FXR-mediated transactivation in an in vitro cis/trans assay (14). In the present issue, the authors determined also whether the expression of the small heterodimer partner (SHP), another nuclear receptor and well-characterized FXR target gene, is regulated by androsterone. They show that the treatment of castrated male mice or mouse AML-12 hepatocytes with androsterone indeed induces SHP mRNA expression, suggesting that androsterone increases the activity of mouse FXR. Using nuclear magnetic resonance spectroscopy technology, the authors show that androsterone directly binds to the ligand binding domain of human FXR. This binding leads to the simultaneous recruitment of the coactivator peptide steroid receptor coactivator-1.
Androsterone is a steroid hormone without known biological activities. It is a major testosterone degradation product, and its concentration in the circulation reflects the synthesis of male steroid hormones (15). Androsterone seems to have no affinity for the AR and consequently does not modulate the biological activity of this receptor. However, androgen metabolites such as androsterone could have biological activities via binding to other nuclear receptors, as shown here for FXR. These observations thus suggest a biological role for androsterone via FXR activation, on either reproductive functions, the best-known biological activities of steroid hormones, or metabolic pathways regulated by FXR. Androsterone could activate FXR in organs that simultaneously produce testosterone and express FXR but also in other tissues because plasma nonconjugated androsterone concentration reaches 0.5–1.5 nM in men (13).
To date, a role for FXR in the development of male sex organs and/or reproductive functions has not been identified. According to initial reports, FXR seems not to be expressed in the testis (1, 16). However, some observations suggest that FXR could be expressed in the testis of mice (17) and certain reptiles, such as the marbled newt (18). Moreover, FXR has been shown to be involved in the control of the annual testicular cycle in reptiles (18). However, androsterone is also produced in the human adrenal gland, an organ that expresses high levels of FXR (for review, see Ref. 3). Altogether, a role for FXR in the control of reproductive processes appears plausible, but such a role needs to be demonstrated by further studies.
On the other hands, a wealth of data implicates sex hormones in the regulation of metabolic processes not directly related to reproductive functions. These include actions on vascular functions, bone mineralization, and also lipid and carbohydrate metabolism in both males and females. Sex hormones modulate the lipid profile and influence the risk of cardiovascular disease (for review, see Ref. 19). Estrogen treatment reduces low-density lipoprotein cholesterol and increases high-density lipoprotein cholesterol and triglyceride levels (20). A number of studies show gender-specific correlations between plasma androgens levels and metabolic disorders. A decrease in men and an increase in women of plasma testosterone levels are associated with the development of obesity (for review, see Ref. 21), hyperglycemia, and type 2 diabetes (22 ; for review, see Ref. 19). Thus, plasma testosterone levels are directly correlated with the risk of coronary artery disease, especially atherosclerosis (for review, see Ref. 23). FXR regulates lipid and glucose metabolism (for review, see Ref. 3), and an antiatherosclerotic activity of FXR has been proposed recently (24). Androsterone could thus modulate FXR activity in vivo and consequently affect metabolic pathways via activation of this nuclear receptor.
The main next step is to establish whether androsterone is not only a natural but also a real endogenous FXR ligand. What are the physiological consequences of FXR activation by androsterone? This could be tested by treating wild-type and FXR–/– mice with androsterone and comparing the responses of these two genotypes. Such study could be completed by analyzing the phenotype after castration of male mice. Using such models, the impact on metabolic processes, such as lipid and glucose homeostasis, could be studied after androsterone treatment. Analysis of mouse models of metabolic disorders could provide additional information. Moreover, studies testing the effects of androsterone on reproductive functions could provide a first track to identify a new role of FXR.
Finally, the identification of androsterone as a new FXR ligand offers a new pharmacological approach to modulate in vivo FXR activity. An important aspect of the study of Wang et al. (12) is that androsterone does not regulate the expression of the same genes as chenodeoxycholic acid, the most efficient bile acid FXR activator. Whereas both ligands induce SHP mRNA expression, only chenodeoxycholic acid, but not androsterone, induces the expression of apolipoprotein CII, an apolipoprotein involved in triglyceride metabolism. These different natural FXR ligands thus seem to behave as selective modulators of FXR activity, yielding distinct patterns of gene regulation. As such, androsterone is a new selective bile acid receptor modulator, a concept that has been proposed by several authors (25). It can thus be anticipated that androsterone will have distinct biological activities as the bile acid FXR activators.
In conclusion, Wang et al. (12) identify androsterone as a new natural ligand of FXR. The biological activities of this testosterone metabolite are currently unknown and the physiological consequences of FXR activation by this ligand remain to be studied.
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Disclosure summary: all authors have nothing to declare.
Abbreviations: AR, Androgen receptor; FXR, farnesoid X receptor; SHP, small heterodimer partner.
Received May 25, 2006.
Accepted for publication May 26, 2006.
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) and farnesoid X-activated receptor (FXR) in the marbled newt along the annual cycle. Mol Reprod Dev 62:216–222[CrossRef][Medline]This article has been cited by other articles:
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  O. V. Belyaeva, S. V. Chetyrkin, A. L. Clark, N. V. Kostereva, K. S. SantaCruz, B. M. Chronwall, and N. Y. Kedishvili Role of Microsomal Retinol/Sterol Dehydrogenase-Like Short-Chain Dehydrogenases/Reductases in the Oxidation and Epimerization of 3{alpha}-Hydroxysteroids in Human Tissues Endocrinology, May 1, 2007; 148(5): 2148 - 2156. [Abstract] [Full Text] [PDF]
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